Adenosine Receptor Subtypes and Cardioprotection

Brief ischemia prior to a sustained period of ischemia reduces myocardial infarct size, a phenomenon known as preconditioning. A cardiac ventricular myocyte model has been developed to investigate the role and signaling mechanism of adenosine receptor subtypes in cardiac preconditioning. A 5-min exposure of cardiac myocytes to simulated ischemia, termed preconditioning ischemia, prior to a subsequent 90-min period of ischemia protected them against injury incurred during the 90-min ischemia. Preconditioning ischemia preserved ATP content, reduced percentage of cells killed, and decreased release of creatine kinase into the medium. Activation of the adenosine A₁ receptor with CCPA or the A₃ receptor with IB-MECA can replace preconditioning ischemia and mimic the protective effect of preconditioning ischemia. Blockade of the A₁ receptor with its selective antagonist DPCPX or of the A₃ receptor with the A₃ selective antagonist MRS1191 during the preconditioning ischemia resulted in only a partial attenuation of the subsequent protection. Incubation with both DPCPX and MRS1191 or with the nonselective antagonist 8-SPT during the preconditioning ischemia completely abolished the protective effect of preconditioning ischemia. The K_ATP channel opener pinacidil caused a large activation of the K_ATP channel current and was able to precondition the myocyte. The K_ATP channel antagonist glibenclamide blocked the cardioprotective effect of preconditioning ischemia when it was included during myocyte exposure to the preconditioning ischemia, indicating that K_ATP channel is a requisite effector in mediating preconditioning. A receptor-mediated stimulation of phospholipase C or phospholipase D, with consequent activation of protein kinase C and K_ATP channel, appears to be the signaling mechanism linking adenosine A₁ and A₃ receptors to the induction of preconditioning. A model of how ischemic preconditioning is triggered and mediated is proposed. Evidence is accumulating to support its validity.